rs879254736

chr19-11110652-GGACCAACGAATGCTTGGACAACAACGGCGGCTGTTCCCACGTCTGCAAT-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_000527.5(LDLR):c.946_994del(p.Asn316LeufsTer38) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.68

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 19-11110652-GGACCAACGAATGCTTGGACAACAACGGCGGCTGTTCCCACGTCTGCAAT-G is Pathogenic according to our data. Variant chr19-11110652-GGACCAACGAATGCTTGGACAACAACGGCGGCTGTTCCCACGTCTGCAAT-G is described in ClinVar as [Pathogenic]. Clinvar id is 251565.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11110652-GGACCAACGAATGCTTGGACAACAACGGCGGCTGTTCCCACGTCTGCAAT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.946_994del	p.Asn316LeufsTer38	frameshift_variant, splice_region_variant	7/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.946_994del	p.Asn316LeufsTer38	frameshift_variant, splice_region_variant	7/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

literature only

LDLR-LOVD, British Heart Foundation

Mar 25, 2016

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs879254736; hg19: chr19-11221328;